Leishmaniasis
Leishmaniasis is caused in humans and animals by protozoan parasites from several leishmania species that are transmitted to hosts by the bites of infected female phlebotomine sandflies.
There are three main human forms of leishmaniasis—visceral (often known as kala-azar and the most serious form of the disease), cutaneous (the most common), and mucocutaneous (the most disfiguring). Most leishmaniases are zoonoses (diseases that can be transmitted from animals to humans) and the reservoir hosts include many species of mammals. Dogs are important reservoirs of L. Infantum responsible for visceral leishmaniasis.
Animals can also suffer from visceral, cutaneous and mucocutaneous forms of the disease.
It is estimated that 350 million people are at risk of the disease (most of them are children), with 1.3 million new cases and 20 000 to 30 000 deaths per year. (Leishmaniasis Worldwide and Global Estimates of Its Incidence. Alvar J. et al. (2012) PLoS ONE 7(5): e35671. doi:10.1371/journal.pone.0035671) Current treatments have serious drawbacks in terms of efficacy, safety, drug resistance, stability, cost and the majority lack an oral dosing option (Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development. Seifert K., Open Med Chem J. 2011; 5:31-39. doi: 10.2174/1874104501105010031). Geographical efficacy variation in the current treatments has started to be observed—for example, the efficacy of liposomal amphotericin B in East Africa is below what is seen in the Indian sub-continent for the same dosage ((a) Berman J D, Badaro R, Thakur C P, Wasunna K M, Behbehani K, et al. (1998) Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries. Bull World Health Organ 76: 25-32. (b) Eltahir A. G. Khalil, Teklu Weldegebreal, Brima M. Younis et al. Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial. PLOS Neglected Tropical Diseases: published 16 Jan. 2014 (info:doi/10.1371/journal.pntd.0002613). Efficacy rates are also found to vary within Africa (Hailu A, Musa A, Wasunna M, Balasegaram M, Yifru S, et al. (2010) Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial. PLoS Negl Trop Dis 4(10): e709. doi:10.1371/journal.pntd.0000709).
As such there is a real unmet medical need for new oral drugs and combination therapy for the treatment and potential elimination of leishmaniasis in certain geographical areas, requiring the development of multiple new oral agents.
Chagas Disease
Chagas disease is an anthropozoonosis due to the flagellated protozoan parasite Trypanosoma cruzi. It is transmitted to humans and other mammals by infected faeces of a blood-sucking triatominae bug through the insect sting, another skin break or through mucous membranes, including conjunctiva or oral/digestive mucosa, occasionally causing outbreaks with contaminated food. Transmission through blood transfusion, pregnancy and delivery are also possible, and less frequently, through organ transplantation or laboratory accident.
Chagas disease is endemic throughout much of Mexico, Central America, and South America where an estimated 7-8 million people are infected. The triatomine bug thrives under poor housing conditions (for example, mud walls, thatched roofs), so in endemic countries, people living in rural areas are at greatest risk for acquiring infection. The recent migration of populations from countries endemic for the disease has increased the geographic distribution of Chagas disease, so that it is now becoming an important health issue in the USA and Canada and in many parts of Europe and the western Pacific. The most common destination for migrants from Latin America is the USA, where more than three hundred thousand individuals are infected with T. cruzi. Spain has the second highest number of infected immigrants, an estimated sixty-seven thousand patients. Approximately thirteen thousand die each year from the complications of Chagas-induced heart disease—a result of the chronic infection.
Chagas disease presents itself in 2 phases. The initial, acute phase lasts for about 2 months after infection. During the acute phase, a high number of parasites circulate in the blood. In most cases, symptoms are absent or mild, but can include fever, headache, enlarged lymph glands, pallor, muscle pain, difficulty in breathing, swelling and abdominal or chest pain. Manifestations of the acute disease resolve spontaneously in about 90% of infected individuals even if the infection is not treated with trypanocidal drugs. About 60-70% of these patients will never develop clinically apparent disease. These patients have the indeterminate form of chronic Chagas disease, which is characterised by positivity for antibodies against T. cruzi in serum, a normal 12-lead electrocardiogram (ECG), and normal radiological examination of the chest, oesophagus, and colon. The remaining 30-40% of patients will subsequently develop a determinate form of chronic disease.
Up to 30% of patients with the determinate form may suffer from cardiac disorders and up to 10% from digestive (typically enlargement of the oesophagus or colon), neurological or mixed alterations or disorders. The infection can lead to sudden death or heart failure caused by progressive destruction of the heart muscle.
There is currently no vaccine for Chagas disease. Chemotherapy options are limited: benznidazole and nifurtimox are the only trypanocidal drugs available with proven efficacy against Chagas disease. Both medicines are almost 100% effective in curing the disease if given soon after infection at the onset of the acute phase. However, while studies have shown that these nitroderivatives can reduce parasitaemia in the chronic indeterminate form of the disease, clear evidence of their impact on patient-related outcomes remains elusive.
Furthermore, benznidazole and nifurtimox are not consistently used in part because of their substantial side effects (peripheral neurotoxicity, digestive system irritation and serious dermatological conditions).
Newer, safer and more efficacious treatments for Chagas disease are urgently needed.
Human African Trypanosomiasis (HAT) Human African Trypanosomiasis (HAT), also called African sleeping sickness, is a parasitic disease caused by the protozoa Trypanosoma brucei and transmitted by infected tsetse flies (Glossina spp.), from mother to child during pregnancy and can be mechanically transmitted through blood products.
Two forms of disease exist depending on the parasite sub-species:                Trypanosoma brucei gambiense (T.b. gambiense) occurring in west and central Africa, represents approximately 95% of the reported cases of sleeping sickness and causes a chronic infection. A person can be infected for months or even years without major signs or symptoms of the disease. When symptoms emerge, the patient is often already in stage 2 disease.        Trypanosoma brucei rhodesiense (T.b. rhodesiense) is found in eastern and southern Africa and represents approximately 5% of the reported cases. This sub-species of the parasite causes an acute infection. First signs and symptoms of stage 2 disease are observed a few months or weeks after infection.        
The disease progresses through two distinct stages. Stage 1 is the initial haemolymphatic phase of infection and presents with non-specific symptoms including fever, rash, and fatigue. Untreated stage 1 HAT results in stage 2 disease or neurological phase, where parasites invade the central nervous system causing severe neurological symptoms and eventually death. Disturbance of the sleep cycle, which gives the disease its name, is an important feature of this second stage.
Currently four drugs are registered for the treatment of sleeping sickness. They showed different efficacy profiles depending on the T. brucei subspecies and the stage of the disease. The current standard treatment for stage 1 is intravenous or intramuscular pentamidine (for T. b. gambiense), or intravenous suramin (for T. b. rhodesiense). For stage 2, the front line treatment is intravenous melarsoprol, intravenous eflornithine only, or eflornithine in combination with nifurtimox. Intravenous melarsoprol in combination with oral nifurtimox may also be used. All drugs suffer from undesirable and in some cases serious adverse effects.
Safer and more efficacious treatments for HAT are urgently needed.
Animal African Trypanosomiasis (AAT)
Animal trypanosomiasis is also known as Animal African trypanosomiasis (AAT), and is a disease of vertebrate non-human animals. Human African trypanosomiasis (HAT) is commonly known as sleeping sickness. Animal trypanosomiasis is caused by various parasite species and sub-species of the Trypanosoma genus, trypanosomes that are pathogenic to animals, including Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and Trypanosoma evansi. It is thought that there are likely further, un-identified trypanosome species or sub-species that are pathogenic to animals and also cause animal trypanosomiasis. Trypanosomes are protozoan parasites in the family Trypanosomatidae and most trypanosomes are transmitted by tsetse flies with the trypanosomes infecting the blood of the animal. As such, an infected animal can act as a disease reservoir with resultant potential for further disease spread in areas affected by the tsetse fly. In Africa, the disease is most common in areas affected by tsetse flies and is spread by the bite of an infected tsetse or other infected flies. Many different animals can be infected by animal trypanosomiasis, including domestic livestock, such as cattle, goats, pigs, sheep and camels. Wild animals, including elephants and leopards have also been found to have trypanosomiasis. Different parasites affect different ranges of organism. Animals are primarily at risk from this disease wherever trypanosomes and the tsetse fly vector exist, and in Africa this “tsetse belt” is between latitude 15° N and 29° S, from the southern edge of the Sahara desert to Zimbabwe, Angola and Mozambique.
In cattle the disease is frequently fatal unless treated. The symptoms include loss of condition, severe weight loss/emaciation, anaemia and fever. Current treatments for animal trypanosomiasis were introduced more than 50 years ago with isometamidium chloride, ethidium bromide and diminazene acetate forming the main treatments at present. However, as discussed by Chitanga et al, in recent years there have been increasing problems due to resistance to the presently available treatments, Chitanga et al., “High Prevalence of Drug Resistance in Animal Trypanosomes with a History of Drug Exposure”. PLoS Neglected Tropical Diseases, 2011, 5, e1454.
The disease is a particular problem in sub-Saharan Africa, where it is commonly referred to as AAT, nagana, or nagana pest, and has a major effect on agriculture. In regions where herds are affected, not only are meat and milk production significantly reduced, but also the use of infected animals for vital tasks such as ploughing are compromised. Bouyer et al. “Community- and farmer-based management of animal African trypanosomiasis in cattle”. Trends in Parasitology, 2013, 29, 519-522.
Thus it would be of great economic benefit to cattle farmers in regions affected by animal trypanosomiasis, and particularly farmers in sub-Saharan Africa to provide an improved treatment for AAT, an improved AAT treatment suitable for intramuscular injection, an improved AAT treatment suitable for intramuscular injections formulated as a single-dose for direct action (treatment of an infected animal) and/or prophylactic utility (uninfected animal).
Thus there is a need for new and effective anti-animal trypanosomiasis agents. In particular there is a need for new anti-animal trypanosomiasis agents which: are effective against Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and/or Trypanosoma evansi infections; are effective against drug-resistant Trypanosoma congolense and/or Trypanosoma vivax; have transmission-blocking potential; which can be formulated for pharmaceutical or veterinary use, such as for intramuscular or oral administration; or which can be formulated for subcutaneous injection; or further which can be used for single-dose treatment; or which can be used for prophylactic treatment.
WO 2014/151784 and US 2014/0275119 disclose certain imidazopyrimidine compounds useful for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as Leishmaniasis, Human African Trypanosomiasis and Chagas disease.
WO 2014/151630 and US 2014/0275013 disclose certain compounds useful for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as Leishmaniasis, Human African Trypanosomiasis and Chagas disease.
WO 2015/095477 and US 2015/175613 disclose certain [1,2,4]triazolo[1,5-a]pyrimidine compounds useful for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as Leishmaniasis, Human African Trypanosomiasis and Chagas disease.
US 2008/0039457 discloses certain [1,2,4]triazolo[4,3-b][1,2,4triazine compounds useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.